Inflammation plays an important role in the etiology and pathophysiology of spontaneous preterm birth (SPTB), and selenoprotein S (SEPS1) is involved in regulating the inflammatory response. Recently the G-105A promoter polymorphism in SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined whether this functional polymorphism was related to the risk of SPTB in a Chinese population. We also examined the impact of premature rupture of membranes (PROM) on susceptibility to SPTB. The SEPS1 G-105A polymorphism was genotyped in 569 preterm singleton neonates and 673 term neonates by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. χ (2) tests and logistic regression analyses were used to calculate the odds ratios (ORs) and 95%... confidence intervals (95% CIs). We observed that, compared with the GG genotype, -105A positive genotypes (GA + AA genotypes) were associated with significantly increased susceptibility to SPTB (adjusted OR, 1.87; 95% CI, 1.36-2.57; P<0.001). The -105A positive genotypes were also significantly associated with increased susceptibility to SPTB, both in the patients with PROM (adjusted OR, 2.65; 95% CI, 1.73-4.03; P<0.001) and in those without PROM (adjusted OR, 1.56; 95% CI, 1.09-2.24; P = 0.015). The -105A positive genotypes were also significantly associated with increased susceptibility to SPTB between extremely preterm neonates and controls (adjusted OR, 4.46; 95% CI, 1.86-10.73; P = 0.002) and between moderately preterm neonates and controls (adjusted OR, 1.76; 95% CI, 1.25-2.47; P = 0.001). Our findings suggest that the SEPS1 G-105A polymorphism contributes to the risk of developing SPTB in a Chinese population.